Inhibition of matrix metalloproteinases (MMPs) as an approach to treat diseases such as cancer, arthritis or multiple sclerosis is now an area of intense interest within the pharmaceutical industry (see P. R. Beckett & M. Whittaker in Exp. Opin. Ther. Patents (1998) 8, 259-282).
MMPs are a family of zinc-containing calcium dependent enzymes, including stromelysins, collagenases and gelatinases. Approximately nineteen MMPs have been identified. MMPs are capable of degrading and remodeling many proteinaceous components of the extracellular matrix in both physiological and pathological conditions. Misregulation and overexpression of MMPs is believed to be a major factor in a number of disease states, most of them characterized by unwanted degradation of connective tissue. These include rheumatoid arthritis, tumor invasion, metastasis, angiogenesis, multiple sclerosis, periodontal disease, coronary artery disease, restenosis, congestive heart failure, wound healing, bone matrix degradation, osteoporosis, liver cirrhosis, cerebral ischemia, meningitis and others.
Other zinc-containing proteinases include Angiotensin Converting Enzyme (ACE), Endothelin Converting Enzyme (ECE) and Adamalysins, the inhibition of which may be of considerable clinical importance.
Compounds that contain a zinc binding function may prevent the catalytic activity of zinc-containing proteinases, for example of MMPs, since they block the zinc atom from fulfilling its catalytic role at the enzyme's active site. MMP (and other zinc-containing proteinases) inhibiting activity has been found in certain hydroxamates, sulfonamide hydroxamates, phosphonates, phosphinates, phosphonamidates, thiols, carboxylates or peptides (P. R. Beckett & M. Whittaker in Exp. Opin. Ther. Patents (1998) 8, 259-282).
Alpha-oxophosphonates, also known such as acylphosphonates have been shown to be capable to chelate various metal ions, such as calcium (M. Mathew et al, Inorg. Chem. (1998) 37, 6485-6494). However, there is no existing record showing that alpha-oxophosphonates inhibit MMPs or other zinc-containing proteinases.
Phosphonoformyl amine derivatives were described in P. Wieczorek et al, Pestic. Sci. (1994), 40 57-62 as having herbicidal activity. In addition, N-phosphonoformyl amino acid derivatives were described in DD 242811 as having antiviral activity.